Traditional processes of drug discovery involve the screening of complex fermentation broths and plant extracts for a desired biological activity or the chemical synthesis of many new compounds for evaluation as potential drugs. The advantage of screening mixtures from biological sources is that a large number of compounds are screened simultaneously, in some cases leading to the discovery of novel and complex natural products with activity that could not have been predicted otherwise. The disadvantages are that many different samples must be screened and numerous purifications must be carried out to identify the active component, often present only in trace amounts. On the other hand, laboratory syntheses give unambiguous products, but the preparation of each new structure requires significant amounts of resources. Generally, the de nova design of active compounds based on the high resolution structures of enzymes has not been successful.
It is thus now widely appreciated that combinatorial libraries are useful per se and that such libraries and compounds comprising them have great commercial importance. Indeed, a branch of chemistry has developed to exploit the many commercial aspects of combinatorial libraries.
In order to maximize the advantages of each classical approach, new strategies for combinatorial deconvolution have been developed independently by several groups. Selection techniques have been used with libraries of peptides (Geysen, H. M., Rodda, S. J., Mason, T. J., Tribbick, G. and Schoofs, P. G., J. Immun. Meth. 1987, 102, 259-274; Houghten, R. A., Pinilla, C., Blondelle, S. E., Appel, J. R., Dooley, C. T. and Cuervo, J. H., Nature, 1991, 354, 84-86; Owens, R. A., Gesellchen, P. D., Houchins, B. J. and DiMarchi, R. D., Biochem. Biophys. Res. Commun., 1991, 181, 402-408; Doyle, M. V., PCT WO 94/28424; Brennan, T. M., PCT WO 94/27719); nucleic acids (Wyatt, J. R., et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 1356-1360; Ecker, D. J., Vickers, T. A., Hanecak, R., Driver, V. and Anderson, K., Nucleic Acids Res., 1993, 21, 1853-1856); nonpeptides and small molecules (Simon, R. J., et al., Proc. Natl. Acad. Sci. USA, 1992, 89, 9367-9371; Zuckermann, R. N., et al., J. Amer. Chem. Soc., 1992, 114, 10646-10647; Bartlett, Santi, Simon, PCT W091/19735; Ohlmeyer, M. H., et al., Proc. Natl. Acad. Sci. USA, 1993, 90, 10922-10926; DeWitt, S. H., Kiely, J. S., Stankovic, C. J., Schroeder, M. C. Reynolds Cody, D. M. and Pavia, M. R., Proc. Natl. Acad. Sci. USA, 1993, 90, 6909-6913; Cody et al., U.S. Pat. No. 5,324,483; Houghten et al., PCT WO 94/26775; Ellman, U.S. Pat. No. 5,288,514; Still et al., PCT WO 94/08051; Kauffman et al., PCT WO 94/24314; Carell, T., Wintner, D. A., Bashir-Hashemi, A. and Rebek, J., Angew. Chem. Int. Ed. Engel., 1994, 33, 2059-2061; Carell, T., Wintner, D. A. and Rebek, J., Angew. Chem. Int. Ed. Engel., 1994, 33, 2061-2064; Lebl, et al., PCT WO 94/28028). A review of the above references reveals that the most advanced of these techniques are those for selection of peptides and nucleic acids. Several groups are working on selection of heterocycles such as benzodiazepines. With the exception of Rebek et al., scant attention has been given to combinatorial discovery of other types of molecules.
The majority of the techniques reported to date involve iterative synthesis and screening of increasingly simplified subsets of oligomers. Monomers or sub-monomers that have been utilized include amino acids, amino acid-like molecules, i.e. carbamate precursors, and nucleotides, both of which are bifunctional. Utilizing these techniques, libraries have been assayed for activity in either cell-based assays, or for binding and/or inhibition of purified protein targets.
A technique, called SURF(trademark) (Synthetic Unrandomization of Randomized Fragments), involves the synthesis of subsets of oligomers containing a known residue at one fixed position and equimolar mixtures of residues at all other positions. For a library of oligomers four residues long containing three monomers (A, B, C), three subsets each containing 27 compounds would be synthesized (NNAN, NNBN, NNCN, where N represents equal incorporation of each of the three monomers). Each subset is then screened in a functional assay and the best subset is identified (e.g. NNAN). A second set of subsets is synthesized and screened, each containing the fixed residue from the previous round, and a second fixed residue (e.g. ANAN, BNAN, CNAN, each containing 9 molecules). Through successive rounds of screening and synthesis, a unique sequence with activity in the functional assay can be identified. The SURF(trademark) technique is described in Ecker, D. J., Vickers, T. A., Hanecak, R., Driver, V. and Anderson, K., Nucleic Acids Res., 1993, 21, 1853-1856. The SURF(trademark) method is further described in PCT patent application WO 93/04204, the entire disclosure of which is herein incorporated by reference.
The combinatorial chemical approach that has been most utilized to date, utilizes an oligomerization from a solid support using monomeric units and a defined connecting chemistry, i.e. a solid support monomer approach. This approach has been utilized in the synthesis of libraries of peptides, peptoids, carbamates and vinylogous peptides connected by amide or carbamate linkages or nucleic acids connected by phosphate linkages as exemplified by the citations in previous paragraphs above. A mixture of oligomers (pool or library) is obtained from the addition of a mixture of activated monomers during the coupling step or from the coupling of individual monomers with a portion of the support (bead splitting) followed by remixing of the support and subsequent splitting for the next coupling. In this monomeric approach, each monomeric unit would carry a tethered letter, i.e., a functional group for interaction with the target. Further coupling chemistry that allows for the insertion of a tethered letter at a chemically activated intermediate stage is referred to as the sub-monomer approach.
The diversity of the oligomeric pool is represented by the inherent physical properties of each monomer, the number of different monomers mixed at each coupling, the physical properties of the chemical bonds arising from the coupling chemistry (the backbone), the number of couplings (length of oligomer), and the interactions of the backbone and monomer chemistries. Taken together, these interactions provide a unique conformation for each individual molecule.
There remains a need in the art for molecules which have fixed preorganized geometry that matches that of targets such as proteins and enzymes, nucleic acids, lipids and other targets. The backbone of such molecules should be rigid with some flexibility, and such molecules should be easy to construct via automated synthesis on solid support.
In accordance with this invention there are provided oligomeric compounds and libraries of such compounds comprising a plurality of aminodiol monomer subunits joined by linking groups, wherein each of said aminodiol monomer subunits has one of the structures I, II, III, IV, V, VI, VII, VIII, IX, X, or XI; 
wherein:
each x is, independently, 0 to 5;
na, nb and nc are each, independently, 0 to 2, where the sum of na, nb and nc is from 1 to 5;
R1 is xe2x80x94Txe2x80x94L or a base labile protecting group;
T is a single bond, a methylene group or a group having formula:
{[CR6R7]mxe2x80x94(R5)xe2x80x94[CR8R9]nxe2x80x94[C(R10)]pxe2x80x94(E)xe2x80x94}qxe2x80x94
where:
R10 is xe2x95x90O, xe2x95x90S, or xe2x95x90NR11;
R5 and E, independently, are a single bond, CHxe2x95x90CH, C∇C, O, S, NR11, or C6-C14 aryl;
each R6, R7, R8, R9, R11, R12 and R13 are, independently, H, alkyl or haloalkyl having 1 to about 10 carbon atoms, alkenyl having 2 to about 10 carbon atoms, alkynyl having 2 to about 10 carbon atoms, or aryl having 7 to about 14 carbon atoms;
m and n, independently, are 0 to 5;
p is 0 or 1;
q is 1 to about 10;
L is H, substituted or unsubstituted C2-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C4-C7 carbocyclic alkyl, substituted or unsubstituted C4-C7 carbocyclic alkenyl, substituted or unsubstituted C4-C7 carbocyclic alkynyl, substituted or unsubstituted C6-C14 aryl, an ether having 2 to 10 carbon atoms and 1 to 4 oxygen or sulfur atoms, a nitrogen containing heterocycle, a sulfur containing heterocycle, an oxygen containing heterocycle, a metal coordination group, a conjugate group, halogen, hydroxyl (OH), thiol (SH), keto (Cxe2x95x90O), carboxyl (COOH), amide (CONR12), amidine (C(xe2x95x90NH)NR12R13), guanidine (NHC(xe2x95x90NH)NR12R13), glutamyl (R12OOCCH(NR12R13)(CH2)2C(xe2x95x90O), nitrate (ONO2), nitro (NO2), nitrile (CN), trifluoromethyl (CF3), trifluoromethoxy (OCF3), O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, NH-aralkyl, amino (NH2), azido (N3), hydrazino (NHNH2), hydroxylamino (ONH2), sulfoxide (SO), sulfone (SO2), sulfide (Sxe2x80x94), disulfide (Sxe2x80x94S), silyl, a nucleosidic base, an amino acid side chain, a carbohydrate, a biopharmaceutically active moiety, or group capable of hydrogen bonding where the substituent groups are selected from hydroxyl, amino, alkoxy, alcohol, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, and alkynyl groups;
R2 is hydrogen or C1-C10 alkyl;
R3 and R4 are independently hydrogen, an acid labile hydroxyl protecting group, a linking group or a conjugate group, wherein said linking group has the formula: 
wherein:
J1 is xe2x95x90O or xe2x95x90S;
J2 is OH or N(Y0)T0;
Y0 is H or [Q2]jxe2x80x94Z2;
T0 is [Q1]kxe2x80x94Z1, or together Y0 and T0 are joined in a nitrogen heterocycle;
Q1 and Q2 independently are C2-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C4-C7 carbocylo alkyl C4-C7 carbocylo alkenyl, a heterocycle, an ether having 2 to 10 carbon atoms and 1 to 4 oxygen or sulfur atoms, a polyalkyl glycol, or C7-C14 aralkyl;
j and k independently are 0 or 1;
Z1 and Z2 independently are H, C1-C2 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C6-C14 aryl, C7-C15 aralkyl, halogen, CHxe2x95x90O, OR12, SR12, NR12R13, C(xe2x95x90NH)NR12R13, CH(NR12R13), NHC(xe2x95x90NH)NR12R13, CH(NH2)C(xe2x95x90O)OH, C(xe2x95x90O)NR12R13, C(xe2x95x90O)OR12, a metal coordination group, a reporter group, a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, or a polyethylene glycol group; and
provided that at least one of said aminodiol monomer subunits in said oligomeric compound does not have structure III.
Further in accordance with this invention there are provided processes for preparing oligomeric compounds and libraries of such compounds comprising:
(a) selecting an aminodiol monomer subunit having the structure I, II, III, IV, V, VI, VII, VIII, IX, X, or XI: 
wherein:
each x is, independently, 0 to 5;
na, nb and nc are each, independently, 0 to 2, where the sum of na, nb and nc is from 1 to 5;
R1 is a base labile protecting group;
R2 is hydrogen or C1-C10 alkyl; and
one of R3 or R4 is hydrogen or an activated phosphite group and the other of R3 or R4 is an acid labile hydroxyl protecting group;
(b) attaching said aminodiol monomer subunit to a solid support to form a solid support bound aminodiol monomer subunit;
(c) treating said acid labile hydroxyl protecting group with a dilute acid to form a free hydroxyl group,
(d) reacting said free hydroxyl group with a further aminodiol monomer subunit having structure I, II, III, IV, V, VI, VII, VIII, IX, X, or XI, thereby forming an oligomeric compound bound to said solid support, said oligomeric compound containing a phosphite linkage;
(e) optionally iteratively repeating steps (c) and (d) to increase the length of the oligomeric compound bound to said solid support;
(f) optionally, prior to step (c) or after step (d) oxidizing said phosphite linkage to form a phosphate linking group wherein said linking groups are selected having formula: 
wherein:
J1 is xe2x95x90O or xe2x95x90S;
J2 is OH or N (Y0)T0;
Y0 is H or [Q2]jxe2x80x94Z2;
T0 is [Q1]kxe2x80x94Z1, or together Y0 and T0 are joined in a nitrogen heterocycle;
Q1 and Q2 independently, are C2-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C4-C7 carbocylo alkyl or alkenyl, a heterocycle, an ether having 2 to 10 carbon atoms and 1 to 4 oxygen or sulfur atoms, a polyalkyl glycol, or C7-C14 aralkyl;
j and k independently, are 0 or 1;
Z1 and Z2 independently are H, C1-C2 alkyl, C2-C10 alkenyl, C2-C20 alkynyl, C6-C14 aryl, C7-C15 aralkyl, halogen, CHxe2x95x90O, OR12, SR12, NR12R13, C(xe2x95x90NH)NR12R13, CH(NR12R13), NHC(xe2x95x90NH)NR12R13, CH(NH2)C(xe2x95x90O)OH, C(xe2x95x90O)NR12R13, C(xe2x95x90O)OR12, a metal coordination group, a reporter group, a nitrogen-containing heterocycle, a purine, a pyrimidine, a phosphate group, a polyether group, or a polyethylene glycol group; and
(g) prior to step (e) or after step (f) contacting said solid support bound aminodiol monomer subunit or said support bound oligomeric compound with a base to remove said base labile amino protecting group to form the solid support bound aminodiol monomer subunit or support bound oligomeric compound having a free amine, and derivatizing said free amine with a group of the formula -T-L;
wherein:
T is a single bond, a methylene group or a group having formula:
{[CR6R7]mxe2x80x94(R5)xe2x80x94[CR8R9]nxe2x80x94[C(R10)]p-(E)-}q-
where:
R10 is xe2x95x90O, xe2x95x90S, or xe2x95x90NR11;
R5 and E, independently, are a single bond, CHxe2x95x90CH, Cxe2x89xa1C, O, S, NR11, or C6-C14 aryl;
each R6, R7, R8, R9, R11, R12 and R13 are, independently, H, alkyl or haloalkyl having 1 to about 10 carbon atoms, alkenyl having 2 to about 10 carbon atoms, alkynyl having 2 to about 10 carbon atoms, or aryl having 7 to about 14 carbon atoms;
m and n, independently, are 0 to 5;
p is 0 or 1;
q is 1 to about 10;
L is H, substituted or unsubstituted C2-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C4-C7 carbocyclic alkyl, substituted or unsubstituted C4-C7 carbocyclic alkenyl, substituted or unsubstituted C4-C7 carbocyclic alkynyl, substituted or unsubstituted C6-C14 aryl, an ether having 2 to 10 carbon atoms and 1 to 4 oxygen or sulfur atoms, a nitrogen containing heterocycle, a sulfur containing heterocycle, an oxygen containing heterocycle, a metal coordination group, a conjugate group, halogen, hydroxyl (OH), thiol (SH), keto (Cxe2x95x90O), carboxyl (COOH), amide (CONR12), amidine (C(xe2x95x90NH)NR12R13), guanidine (NHC(xe2x95x90NH)NR12R13), glutamyl (R12OOCCH(NR12R13)(CH2)2C(xe2x95x90O), nitrate (ONO2), nitro (NO2), nitrile (CN), trifluoromethyl (CF3), trifluoromethoxy (OCF3), O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aralkyl, S-aralkyl, NH-aralkyl, amino (NH2), azido (N3), hydrazino (NHNH2), hydroxylamino (ONH2), sulfoxide (SO), sulfone (SO2), sulfide (Sxe2x80x94), disulfide (Sxe2x80x94S), silyl, a nucleosidic base, an amino acid side chain, a carbohydrate, a biopharmaceutically active moiety, or group capable of hydrogen bonding where the substituent groups are selected from hydroxyl, amino, alkoxy, alcohol, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, and alkynyl groups;
(h) optionally repeating steps (c) and (d) followed by step (g) to increase the length of the oligomeric compound bound to said solid support;
(i) treating said oligomeric compound bound to said solid support with acid to deprotect any protecting groups; and
(j) cleaving said oligomeric compound from said solid support.